The tumor necrosis factor superfamily includes ligands that bind the corresponding members of the tumor necrosis factor receptor superfamily of receptors. Such members of the receptor superfamily include, for example, tumor necrosis factor receptors (TNFR) (type I or 55K or TNFR60 and type II or 75K or TNFR80), CD30, nerve growth factor receptor, CD27, CD40, CD95/APO-1 or Fas, CD120a, CD120b, lymphtoxin beta receptor (LT beta R), and a TRAIL receptor. The receptors of this family are membrane bound and recognize soluble or membrane bound ligands that mediate diverse cellular responses. The corresponding ligands for these receptors include in some cases membrane or soluble forms and include, for example, tumor necrosis factor alpha (TNFα), CD30 ligand, nerve growth factor, CD70/CD27 ligand, CD40 ligand, Fas ligand, and TNF-related apoptosis-inducing ligand TRAIL (as described in Wiley et al, Immunity 3:673-82 (1995)). The ligands of the superfamily, including Fas ligand, are type II transmembrane glycoproteins with beta strands that form a jelly-roll beta-sandwich as described in Lotz et al, J. of Leukocyte Biol 60: 1-7 (1996), which is hereby incorporated by reference. Treatment of autoimmune diseases present a unique challenge to molecular biology and medical research. Autoimmune diseases affect between 5 and 7% of the human population, often causing chronic debilitating illnesses, as described in Kuby, IMMUNOLOGY, (W. H. Freeman, N.Y. 1992).
Although precise details of an autoimmune response are incompletely understood, the outcome of antigenic stimulation, whether antibody formation or activated T-cells, or tolerance, seems to depend on the same factors whether a reaction to auto-antigen or exogenous antigen, as described in THE MERCK MANUAL, 16th edition (Merck & Co. Inc. 1992). Also described in THE MERCK MANUAL are four classes of auto-antigens. Class 1 is antigens from intracellular regions of the cells of the body that, by virtue of their sequestration from the immune system, are not recognized as “self” in the body once secreted. For example, sympathetic ophthalmia causes the release of eye antigens, and a subsequent self reaction to the antigen. Class 2 is represented by self antigens that may become immunogenic by chemical, physical, or biological alteration, for example, when a chemical couples to a self antigen and produces a “foreign” reaction, for example in contact dermatitis and hypersensitivity to drugs. Class 3 is represented by foreign antigen that cross reacts with self antigen, and induces a self reaction to the self antigen, for example, as shown with the development of encephalitis after rabies vaccination. Class 4 is represented by a mutation in immunoincompetent cells, such as the autoimmune phenomena seen with mammals having lymphoma. Finally, an autoimmune reaction may be epiphenomena, developing secondarily after an immune response to an obscure antigen, for example, a virus. All autoimmune diseases have in common an involvement of the immune system, and many involve either activated B-cells, activated T-cells, or both.
Although various ameliorative and palliative therapies exist for some autoimmune diseases, and while the autoimmune diseases can spontaneously regress in a remission, effective treatment has yet to be developed for treating autoimmune diseases. It would be desirable to advance the capacity of medical and clinical research to develop effective treatments of autoimmune diseases by discovery of new methods and new therapeutic agents targeting the molecular biology of autoimmune diseases.